AUTHOR INFORMATION

Section 1 of 10

Authored by Maryam Banikazemi, MD, Assistant Professor, Departments of Neurology and Pediatrics, New York University School of Medicine

Coauthored by Robert J Desnick, MD, PhD, Professor, Chair, Department of Human Genetics, Mount Sinai School of Medicine; Kenneth H Astrin, PhD, Associate Professor of Human Genetics, Department of Human Genetics, Mount Sinai School of Medicine

Edited by Robert D Steiner, MD, Professor, Departments of Pediatrics and Molecular and Medical Genetics, Vice Chair for Research, Head of Division of Metabolism, Department of Pediatrics, Oregon Health & Science University; Director, Consulting Staff, Metabolic Bone Disease Clinic, Shriner's Hospital; Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine.com, Inc; David Flannery, MD, FAAP, FACMG, Vice Chair of Education, Chief, Section of Medical Genetics, Professor, Department of Pediatrics, Medical College of Georgia; Paul D Petry, DO, FACOP, FAAP, Clinical Assistant Professor of Pediatrics, University of North Dakota, School of Medicine and Health Sciences; Consulting Staff, Altru Health System; and Bruce A Buehler, MD, Professor, Department of Pathology and Microbiology, Chairman, Department of Pediatrics, Director, Hattie B Munroe Center for Human Genetics, University of Nebraska Medical Center

Author's Email:	Maryam Banikazemi, MD
Editor's Email:	Robert D Steiner, MD

eMedicine Journal, March 1 2007, VOLUME 8, Number 3

INTRODUCTION

Section 2 of 10

Background: Fabry disease is an X-linked lysosomal storage disease that is caused by deficient activity of lysosomal enzyme a-galactosidase A (a-Gal A). Most males with no a-Gal A activity develop the classic phenotype of Fabry disease, which affects multiple organ systems. The first clinical manifestations of the disease, which consist of episodes of severe pain in the extremities (acroparesthesias), hypohidrosis, corneal and lenticular changes, and skin lesions (angiokeratoma) develop in childhood. The rate of disease progression and specific organ damage demonstrate intrafamilial and interfamilial variability. Renal failure, cardiovascular disease, and stroke are the major causes of morbidity and mortality, occurring in the fourth or fifth decade of life.

Pathophysiology: Glycosphingolipids, predominantly globotriaosylceramide (GL-3) and galabiosylceramide, accumulate in the lysosomes of various cells (eg, in the vascular endothelium of multiple organs) owing to a-Gal A deficiency. The accumulation of GL-3 in the lysosomes causes lysosomal and cellular dysfunction; this, in turn, triggers the cascade of cells and tissue ischemia and fibrosis.

Frequency:

• In the US: Fabry disease is one of the more common lysosomal storage disorders, affecting approximately 1 in 40,000-60,000 males.

Mortality/Morbidity: Prior to the availability of renal transplant, dialysis, and, more recently, enzyme replacement therapy (ERT), the average age at death in men with classic Fabry disease was 41 years. Renal failure, heart failure and/or myocardial infarction, and stroke were among the most likely causes of death.

Race: Although most patients with Fabry disease are white, the disorder has been described in patients in many ethnic groups, including those with Hispanic, African, Asian, and Middle Eastern ancestry.

Sex: As is expected in X-linked disorders, males with deleterious mutations have little-to-no residual a-Gal A activity. Therefore, these patients experience the full spectrum of disease symptoms. Because of random X inactivation (lyonization), the disease presentation in female carriers is more variable and depends on the normal-to-mutant ratio of a-Gal A in the different tissues. A significant number of female carriers may develop Fabry disease–related symptoms, including acroparesthesias, GI symptoms, renal and cardiac disease, and/or stroke.

Age:

• Most males with classic Fabry disease first manifest symptoms in childhood or early adolescence. The earliest manifestations include acroparesthesias, angiokeratomas, hypohidrosis, and lenticular and corneal changes. Proteinuria usually becomes evident in the second decade of life, and renal insufficiency is typically present in the third decade of life. Cardiovascular and cerebrovascular diseases usually develop in the fourth decade of life.

• Individuals with atypical renal or cardiac variants usually do not have signs or symptoms in childhood. Many of these patients remain asymptomatic well into adulthood, when patients with classic symptoms are severely affected or have died from the disease.

CLINICAL

Section 3 of 10

History: Fabry disease should be considered in patients with the isolated features detailed below or in those who show signs of multisystemic involvement in a pattern consistent with renal, cardiac, and cerebrovascular involvement. A detailed and complete medical and family history and thorough physical examination are necessary.

• A detailed medical and family history should be obtained, with emphasis on the following:


• • Presence, location, and density of skin rash (angiokeratoma)
  
  
  
  • Characteristics, frequency, and intensity of pain (acroparesthesia)
  
  
  
  • Bowel habits, abdominal cramping, vomiting, nausea, and food intolerance
  
  
  
  • History of abnormal sweating
  
  
  
  • Heat, cold, and exercise intolerance and easy fatigability
  
  
  
  • Family history of kidney failure, heart disease, stroke, or other signs or symptoms of Fabry disease in X-linked pattern of segregation
  
  
  
• Classic Fabry disease: Patients with classic Fabry disease typically have a-Gal A activity of less than 1% and often demonstrate the full spectrum of symptoms. The 2 categories of classic disease manifestation are as follows:
  • Early manifestations
    • Early manifestations generally begin in childhood or adolescence and include the characteristic corneal and lenticular opacities, skin lesions (angiokeratoma), pain in the extremities (acroparesthesia), and decreased ability to sweat (hypohidrosis). In addition, patients may have chronic abdominal pain and diarrhea. Some patients may experience spontaneous relief of these early symptoms during adulthood (eg, symptomatic improvement of acroparesthesias).

    • The earliest reported symptom of Fabry disease is often intermittent or chronic acroparesthesias. These pain episodes are described as burning, tingling, and numbness and are thought to be related to the involvement of the vascular supply and small fibers of the peripheral nervous system. Pain, especially in the hands and feet, may occur daily and may vary in severity. These episodes may occur in both sexes and may begin as early as age 2 years. Pain may be triggered by a body temperature increase due to exercise, fever, emotional stress, or environmental temperature changes. Extreme pain attacks, referred to as Fabry pain crises, usually affect male patients and are described as severe episodes that last several hours to days. These episodes may be accompanied by low-grade fever, body pains, and fatigue.

    • GI manifestations of Fabry disease are common and are believed to be caused by the deposition of GL-3 in the small vessels and the autonomic ganglia of the intestine. GI symptoms often begin in adolescence and may worsen with age. Common manifestations include episodes of postprandial abdominal pain and bloating, followed by multiple bowel movements, diarrhea, nausea, vomiting, and early satiety. Symptoms are generally more frequent and appear earlier in life in males compared with female carriers.

    • Dermal manifestations of Fabry disease include cutaneous vascular lesions (angiokeratomas) and abnormal sweating (anhidrosis or, more commonly, hypohidrosis). Weakening of the capillary wall and vascular ectasia within the epidermis and dermis causes angiokeratomas. They usually manifest at age 5-13 years and initially appear as small, slightly raised, purplish-red, nonblanching angiectases. The number and size of these lesions progressively increase with age. Anhidrosis or hypohidrosis is also frequently reported and is thought to be secondary to lipid accumulation in the eccrine cells of the sweat glands and dysfunction of the autonomic nervous system.

    • Corneal manifestations are reported in more than 70-90% of patients. The best-known ocular symptom is a pattern of whitish spiral streaks in the corneal epithelium known as cornea verticillata.

    • Some patients may have recurrent fevers with no obvious source. Pain usually accompanies the fevers, and an elevated erythrocyte sedimentation rate may be present.

    • Disease symptoms and implications may affect the patient’s school performance, level of activity, and mental health.

  • Late and serious clinical manifestations of Fabry disease
    • During the late stage of the disease, the progressive deterioration of renal, cardiac, and nervous system function ultimately results in significant morbidity and mortality.

    • Kidney involvement is a prominent feature and is the main cause of premature death in classic Fabry disease. It develops as a result of the progressive accumulation of GL-3 in the renal endothelium and other kidney cell types. Microalbuminuria, proteinuria, and isosthenuria may be apparent in adolescence and early adulthood. Progressive kidney disease is marked by the progression of proteinuria, an increase in serum creatinine levels, and the reduction of the glomerular filtration rate (GFR) during the third decade of life. Long-term hemodialysis is often required, and renal transplantation is usually successful.

    • Fabry-related cardiovascular disease
      • Fabry-related cardiovascular disease is a key cause of premature death.

      • Early signs of cardiac involvement include interventricular septal and left ventricular hypertrophy associated with valvular regurgitation.

      • Clinical signs of congestive heart failure may accompany the progressive concentric LVH and diastolic dysfunction observed in advanced stages of the disease.

      • Mitral valve prolapse and thickening may also be observed.

      • Common initial electrocardiographic abnormalities include sinus bradycardia, nonspecific ST-segment changes, T-wave inversion, and shortened PR interval.

      • Conduction system involvement may be observed as early as the second decade of life, and, as it progresses, the risk of lethal arrhythmias and sudden death increases.

      • Permanent cardiac pacing is needed in approximately 10-20% of patients.

      • Damage to the coronary vascular bed may lead to angina pectoris, variant angina, and myocardial infarction.

      • Predominant involvement of small, penetrating vessels has been reported. This involvement does not necessarily follow the typical patterns observed in atherosclerosis.

    • CNS involvement may be observed on brain MRI as white matter changes. This involvement may be noted as early as the second or third decade of life, typically occurring earlier in males than in females. The primary ischemic-hypoxic damage in CNS results from prothrombotic and occlusive abnormalities, in addition to large-vessel ectasias. Patients may present with transient ischemic attacks, vascular thromboses, seizures, or hemorrhagic or ischemic stroke.

    • Paroxysmal attacks of severe rotational vertigo occur in many patients. Although these episodes are usually brief, some prolonged severe attacks require cessation of activities for several days. Megadolichobasilar compression of the vestibulocochlear nerve has been suggested as a likely cause for these episodes.

    • Sensorineural hearing loss has been frequently documented in patients with Fabry disease and most likely reflects vascular pathology of the inner ear.

    • Peripheral neuropathy in Fabry disease predominantly involves small nerve fibers. The progressive loss of temperature and pain sensation should be assessed during the physical examination.

    • Lymphedema of the legs is a poorly described and a less common manifestation. Often asymmetric, the symptom may start as a transient seasonal event with a tendency to become more severe and extensive over time. This manifestation presumably reflects the progressive GL-3 deposition in the lymphatic vessels and lymph nodes, compromising the lymphatic circulation.

    • Obstructive and constrictive lung diseases have both been documented in a subgroup of patients, often presenting as wheezing, dyspnea, or bronchitis.

    • Priapism has been associated with Fabry disease.

    • Mild anemia is probably due to decreased RBC survival.

    • Poor heat and exercise tolerance is commonly observed in patients. It may start at the early stages of the disease and is reported by both males and females. This poor tolerance is typically attributed to hypohidrosis and acroparesthesias and may become more pronounced in the presence of pulmonary disease or cardiomyopathy in later stages of the disease. Patients may report lack of energy and fatigue.



• Atypical Fabry disease: In atypical cases, individuals with residual enzyme activity demonstrate symptoms later in life, and the symptoms are usually limited to one or a few organs. For example, individuals with atypical cardiac variants usually do not have any signs or symptoms in childhood and present mainly with cardiac disease later in adulthood. In various surveys, approximately 3-12% of patients with unexplained left ventricular hypertrophy (LVH) have been diagnosed with the cardiac variant of Fabry disease.



• Fabry disease in females: Clinical manifestations in female carriers vary greatly because of random X-chromosome inactivation. Although carriers commonly remain asymptomatic throughout life, many demonstrate clinical symptoms as variable and severe as those of affected males. Affected females may experience early manifestations of the disease, such as acroparesthesia and GI discomfort. Their symptoms may also be as severe and progressive as those seen in males (ie, they may develop renal failure). Females who are asymptomatic at the time of initial assessment should be closely and regularly monitored for any evidence of disease manifestation.

Physical:

• Skin symptoms


• • Angiokeratoma, small punctate reddish-to-bluish angiectases, may be either flat or slightly raised and may blanch with pressure. These are commonly observed as dense clusters of lesions on the umbilicus, flanks, thighs, penis, and scrotum.
  
  
  
  • Lesions in the oral mucosa and conjunctiva are observed in some patients.
  
  
  
  • Hypohidrosis and anhidrosis may be observed.
  
  
  
• Visual symptoms


• • Vision is usually not impaired.
  
  
  
  • A slit-lamp examination reveals cornea verticillata, which manifests as whirl-like white-to–golden-brown opacities that extend from the center to the periphery of the cornea. Cornea verticillata is often prominent in female carriers and may play an important role in the early recognition of Fabry disease. Therefore, in females with either a positive family history or symptoms suggestive of Fabry disease, a slit-lamp examination can be very helpful.
  
  
  
  • Other possible ocular findings include lens, retinal and conjunctival changes.
  
  
  
• Neurological symptoms
  • Peripheral neuropathy, specifically loss of temperature and pain sensation, has been reported.

  • Hearing deficit may be observed.



• Lymphedema symptoms: Asymmetric involvement of the lower extremities with pitting edema has been reported in the absence of significant renal or cardiac disease.



• Other symptoms: Characteristic facial appearance, such as coarse facial features, have been described by some authors.

Causes: The gene that encodes a-Gal A has been isolated and sequenced, and more than 245 different mutations (missense, nonsense, splice, deletion, and insertion errors) have been reported. Attempts to correlate genotype with clinical presentation have been confounded by the fact that very few recurrent mutations have been reported. The typical interfamilial variability of the disease phenotype may be due to other modifying factors, which may be genetically or environmentally derived.

WORKUP

Section 4 of 10

Lab Studies:

• a-Gal A activity


• • a-Gal A activity may be measured in plasma, serum, and leukocytes. Tissue biopsies and cultured skin fibroblasts may also be used to measure a-Gal A activity.
  
  
  
  • In males with the classic or variant phenotype, the disease is readily diagnosed based on low a-Gal A activity.
  
  
  
  • Female carriers may have a-Gal A activity that ranges from zero to within the reference range. Thus, enzyme assays are rarely helpful in determining female carrier status.
  
  
  
• DNA analysis: DNA isolated from blood or biopsy specimens can be used for analysis of the a-Gal A gene sequence to identify the disease-causing mutation. DNA testing is the preferred method for identifying and confirming the carrier status of females in whom enzyme activity is within or near the reference range.



• Laboratory tests after diagnosis: After the diagnosis has been confirmed using enzyme assays, DNA testing, or both, carefully assess the patient. A recommended minimum assessment schedule has been developed by the Fabry Board of Advisors ( Eng, 2006)and other experts in the field (Desnick, 2003). The recommended assessment frequency depends on patient age and previous findings. Females and males should undergo the same degree of assessment and monitoring. The following recommended laboratory assessments should be obtained at baseline and at appropriate intervals:


• • CBC count, serum electrolyte level measurement, and lipid profile
  
  
  
  • Renal evaluation
    • Serum BUN and creatinine levels and 24-hour urine or spot urine measurement for total protein/creatinine, albumin/creatinine, sodium, creatinine, and urinary GL-3 (optional) levels

    • Renal biopsy (This may be warranted in atypical cases to exclude any other causes of renal disease.)
  
  
  

Imaging Studies:

• CNS evaluation


• • MRI is used to document evidence of brain ischemic disease.

  • Magnetic resonance angiography (MRA) may be indicated to assess cerebral vasculopathy.

  • Peripheral nerves should be periodically assessed using a detailed neurological examination.

Other Tests:

• Cardiac evaluation


• • Ventricular hypertrophy and septal thickening can be demonstrated using echocardiography. If LVH is present, a cardiac MRI with contrast can be performed to evaluate the presence of scarring.

  • Abnormal ECG findings include sinus bradycardia, nonspecific ST-segment changes, T-wave inversion, and shortened PR interval. Evidence of LVH and previous ischemic injury may also be present.

  • Holter monitoring in selected patients may provide important information.
  
  
  
• Psychosocial evaluation: All health care professionals who treat patients with Fabry disease should be sensitive to the psychosocial burden of a chronic, rare, and progressive disease. In these families, denial, guilt, and anger frequently play a significant role in intrafamilial dynamics. Pay special attention to the history and signs of anxiety disorders, clinical depression, suicidal ideation or attempts, and substance abuse.



• Pulmonary evaluation: Perform induced sputum analysis, lung biopsy, or both if severe pulmonary involvement is present (to exclude an intercurrent disease process).



• Visual evaluation: Perform slit-lamp microscopy to identify the typical Fabry disease–specific changes in the cornea, lens, retina, and conjunctiva.

TREATMENT

Section 5 of 10

Medical Care: Disease management strategies should be tailored to the individual according to patient age and disease stage. These strategies include the use of medication to alleviate the symptoms, disease-specific treatment to delay and prevent possible serious organ damage, and adherence to standard health care measures and a healthy lifestyle.

• Pain management
  • Daily prophylactic doses of neuropathic pain agents (eg, phenytoin, carbamazepine, gabapentin, or a combination of these agents) provide some degree of relief. They are effective in decreasing the frequency and severity of pain episodes or pain crises in most patients.

  • Some patients may require more potent analgesics (eg, opioids) for pain management.



• Management of GI symptoms
  • No specific treatment has been found to control GI symptoms in Fabry disease. However, pancrelipase, metoclopramide, H2 blockers, loperamide, and hydrochloride can ameliorate GI symptoms in some patients.

  • Patients with abdominal symptoms often benefit from a change in eating habits that includes frequent small meals.



• Management of skin symptoms
  • The results of various laser methods used to treat angiokeratomas in patients with Fabry disease have not been promising for patients who are not receiving ERT.

  • Lesions that are more pedunculated may be treated with a series of liquid nitrogen treatments prior to laser therapy.



• Management of visual symptoms: Ocular symptoms in patients with Fabry disease rarely, if ever, cause significant impairment of vision and, as a rule, do not require treatment.

• Management of other symptoms: Symptomatic treatment of renal, cardiovascular, and cerebrovascular complications is warranted.

• Enzyme replacement therapy


• • ERT provides the patient with the biologically functional protein. The infused enzyme is taken up into lysosomes through specific receptors located on the surface of the target cells. Reversal of the metabolic and pathologic abnormalities in the cells and tissues are the key therapeutic goals of ERT. These changes should, in turn, result in improvement of symptoms and prevention of disease complications.

  • Multiple clinical trials with recombinant a-Gal A (agalsidase beta [Fabrazyme]: Genzyme Corporation, Cambridge, Mass; agalsidase alfa [Replagal]: TKT Corporation, Cambridge, Mass) have been performed to investigate the safety and efficacy of ERT in patients with Fabry disease. The outcomes of these clinical studies were the basis for approval of Fabrazyme and Replagal in most European countries in 2001 and for the approval of Fabrazyme in the United States in 2003. The enzyme is administered intravenously. Replagal is administered intravenously at a dose of 0.2 mg/kg every 2 weeks, and Fabrazyme is administered intravenously at a dose of 1 mg/kg every 2 weeks.

  • Initial clinical studies with recombinant a-Gal A showed that ERT is safe and well tolerated, except for mild-to-moderate infusion–associated reactions, which have been managed conservatively. During the phase 3 clinical study, Fabrazyme was shown to clear GL-3 from the plasma and capillary endothelium of the major sites of pathology, such as the kidney, heart, and skin.

  • The clinical benefits of ERT using a-Gal A in patients with advanced Fabry disease were examined in a phase 4 clinical study, which had a double-blind, placebo-controlled design. The rate of progression of renal, cardiac, and cerebrovascular complications and death among patients who received active drug was reduced compared with the placebo group. Therefore, starting ERT immediately after diagnosis to prevent irreversible organ damage is reasonable.

  • The commercial availability of Replagal and Fabrazyme has allowed treatment for many patients around the world. This increased use has enabled further assessment of the effect of ERT on various clinical manifestations of Fabry disease. A growing body of evidence suggests that ERT is beneficial in improving most disease symptoms. However, the response to ERT may vary, depending in part on tissue-specific differences in drug delivery and disease stage. A summary of the effect of ERT on various manifestations as reported by the authors and others is as follows:
    • Improved acroparesthesias

    • Improved GI symptoms

    • Improvement of hypohidrosis and anhidrosis

    • Improvement in the function of C-, –Ad-, and Ab-nerve fibers

    • Stabilization of deteriorating renal function

    • Improved cardiac function

    • Improved lymphedema

    • Improved vertigo

    • Stabilization and occasional improvement in hearing

    • Reduction in stroke frequency

  • Current recommendations suggest that ERT should be initiated as early as possible in all males with Fabry disease (including those with end-stage renal disease). Symptomatic female carriers with serious organ system involvement should also be assessed for ERT administration.

  • The following signs and symptoms suggest serious implications of Fabry disease in females that warrant ERT:
    • Uncontrolled pain at any age that requires alteration of lifestyle and interferes with quality of life

    • Presence of and a progressive increase in proteinuria, exceeding 300 mg per 24 hours or renal biopsy findings that suggest significant renal involvement

    • Patients on dialysis or who have undergone transplantation

    • Ischemic heart disease with or without cardiac dysfunction

    • Moderate-to-severe heart enlargement (ie, LVH)

    • Heart rhythm abnormalities

    • Significant brain involvement or MRI changes

    • Frequent severe vertigo episodes

    • Severe fatigue
  
  
  
• Adjunctive therapies and preventive measures
  • Use of angiotensin-converting enzyme (ACE) inhibitors and/or blockers in patients with proteinuria is the criterion standard. The dose should be optimized by a nephrologist.

  • Control of hypertension is essential.

  • Dyslipidemia (most commonly, hypercholesterolemia) should be treated.

  • Prophylaxis with antiplatelet or anticoagulant medication can be important in patients who have had transient ischemic attacks or a stroke.

  • Permanent cardiac pacing should be considered in high-risk patients.

  • Hearing loss can be treated with hearing aids. Patients should avoid excessive noise exposure.

  • Patients should be encouraged to maintain a healthy lifestyle, such as avoiding smoking.

Surgical Care: In patients who have undergone renal transplantation, engrafted kidneys from unaffected and noncarrier individuals correct kidney function and remain free of GL-3 storage because the transplanted kidney is capable of producing normal levels of a-Gal A. However, other organ system damage continues unabated in patients who have undergone kidney transplantation. In particular, vascular disease of the heart and brain may continue to progress. Thus, these patients should receive or continue to receive ERT.

Consultations: A multidisciplinary team is essential. Emotional support and family counseling should be an integral part of patient care. In addition, providing patients with the resources to learn about Fabry disease and to contact other patients and families struggling with similar issues may help ameliorate feelings of isolation. Consultations should include the following:

• Medical geneticist



• Nephrologist



• Cardiologist



• Ophthalmologist



• Pain specialist



• Neurologist

Diet: A "renal diet" is recommended for patients with proteinuria and renal failure. A nutritionist should supervise a low-protein and low-sodium diet. Patients are advised to monitor their activity level in order to avoid factors that precipitate symptoms. For example, adequate hydration prior to any physical activity and avoidance of exposure to extreme temperatures are recommended to avoid pain.

MEDICATION

Section 6 of 10

Drug Category: Analgesics -- These agents are used to relieve neuropathic pain. Phenytoin and carbamazepine are 2 medications used to treat acroparesthesias in patients with Fabry disease. Either drug may be used, although some patients benefit from a combination.

Drug Name	Phenytoin (Dilantin) -- Used for analgesia for acroparesthesia. May act in the motor cortex, where it may inhibit spread of seizure activity. Activity of the brainstem centers responsible for the tonic phase of grand mal seizures may also be inhibited. Individualize dose. Administer larger dose before bedtime if dose cannot be equally divided.
Adult Dose	300 mg PO qd
Pediatric Dose	100 mg PO qd
Contraindications	Documented hypersensitivity; sinoatrial block; second- and third-degree AV block; sinus bradycardia; Adams-Stokes syndrome
Interactions	Amiodarone, benzodiazepines, chloramphenicol, cimetidine, fluconazole, isoniazid, metronidazole, miconazole, phenylbutazone, succinimides, sulfonamides, omeprazole, phenacemide, disulfiram, ethanol (acute ingestion), trimethoprim, and valproic acid may increase phenytoin toxicity; effects of phenytoin may decrease when taken concurrently with barbiturates, diazoxide, ethanol (chronic ingestion), rifampin, antacids, charcoal, carbamazepine, theophylline, and sucralfate; may decrease effects of acetaminophen, corticosteroids, dicumarol, disopyramide, doxycycline, estrogens, haloperidol, amiodarone, carbamazepine, cardiac glycosides, quinidine, theophylline, methadone, metyrapone, mexiletine, oral contraceptives, and valproic acid
Pregnancy	D - Unsafe in pregnancy
Precautions	Obtain CBC count and urinalyses when therapy is begun and at monthly intervals for several months to monitor for blood dyscrasias; discontinue if rash appears and do not resume use if rash is exfoliative, bullous, or purpuric; rapid IV infusion may result in death from cardiac arrest marked by QRS widening; caution in patients with acute intermittent porphyria and diabetes (may elevate blood sugar levels); discontinue if hepatic dysfunction occurs

Drug Name	Carbamazepine (Tegretol) -- Indicated for complex partial seizures and trigeminal neuralgia. May block posttetanic potentiation by reducing summation of temporal stimulation. May reduce polysynaptic responses and block posttetanic potentiation. Following therapeutic response, may reduce dose to minimum effective level or discontinue treatment at least once every 3 mo. Doses are typically lower than those used to treat seizures and are administered once daily.
Adult Dose	300 mg PO qd
Pediatric Dose	100 mg PO qd
Contraindications	Documented hypersensitivity; bone marrow depression; administration of MAOIs within previous 14 d
Interactions	Serum levels may increase significantly within 30 d of danazol coadministration (avoid when possible); do not coadminister with MAOIs; cimetidine may increase toxicity, especially if taken in first 4 wk of therapy; carbamazepine may decrease primidone and phenobarbital levels (coadministration may increase carbamazepine levels)
Pregnancy	D - Unsafe in pregnancy
Precautions	Do not use to relieve minor aches or pains; caution with increased intraocular pressure; obtain CBC counts and serum-iron baseline before treatment, during first 2 months, and yearly or every other year thereafter; can cause drowsiness, dizziness, and blurred vision; caution while driving or performing other tasks requiring alertness

Drug Name	Gabapentin (Neurontin) -- FDA-approved oral medication for management of postherpetic neuralgia. Also FDA approved for the treatment of partial seizures in adults and children. Chemical structure similar to the inhibitory neurotransmitter GABA. Appears to work by raising GABA levels by some effect on a GABA transporter protein. Also decreases activity of voltage-gated calcium channels via binding to a secondary protein. Approved for epilepsy in children. Available as tab, cap, and liquid dosage forms.
Adult Dose	100-300 mg PO qd initially; may slowly titrate upward as needed for pain; not to exceed 2400 mg/d
Pediatric Dose	<3 years: Not established 3-12 years: Not established; limited data suggests 10-15 mg/kg/d PO divided q8h; may gradually titrate upward at 3-d intervals >12 years: Administer as in adults
Contraindications	Documented hypersensitivity
Interactions	Antacids may significantly reduce bioavailability of gabapentin (administer at least 2 h following antacids); may significantly increase norethindrone levels ; cimetidine, hydrocodone, and morphine may increase gabapentin AUC; naproxen may increase gabapentin absorption
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Common adverse effects include drowsiness, dizziness, somnolence, and unwanted eye movements; children may experience emotional ability hostility, thought disorder, and hyperkinesia; caution in elderly patients and those with severe renal impairment; abrupt withdrawal may precipitate seizures

Drug Category: Enzyme replacement therapy -- a -Gal A deficiency leads to the accumulation of GSLs with terminal a-galactosyl residues. Clinical manifestations of Fabry disease are reflected in the tissue target sites of lipid storage. The recombinantly produced enzyme a-Gal A is available in Europe and United States.

Drug Name	Agalsidase (Fabrazyme, Replagal) -- Recombinant form of the human enzyme a -Gal A, which is deficient in patients with Fabry disease. Data from clinical trials show a decrease in GL-3 levels following enzyme replacement, reversal in lipid tissue storage, stabilized or improved renal and cardiac function, and reduction or relief of neuropathic pain. Following enzyme replacement, the long-term use of neuropathic pain medication has been reduced. Agalsidase beta (Fabrazyme) is manufactured by Genzyme Corporation (Cambridge, Mass) and is based on expression of the human GLA gene in CHO cells. Agalsidase alfa (Replagal) is manufactured by Transkaryotic Therapies, Inc (Cambridge, Mass) and is based on activation of the human GLA gene expression in human (skin) fibroblasts.
Adult Dose	Initial dose: Fabrazyme: 1 mg/kg IV infused over 4-6 h (initial infusion); subsequent infusions may be administered at a rate of 3-5 mg/min; repeat q2wk Replagal: 0.2 mg/kg IV infused over 40 min q2wk Maintenance dose: Not established
Pediatric Dose	Not established; appropriate time to initiate treatment in children has not been determined
Contraindications	Documented hypersensitivity
Interactions	None reported
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	May cause IgG antibody production (55% with Replagal, 83% with Fabrazyme); may cause allergic reactions (10% with Replagal, 59% with Fabrazyme), which are prevented by premedication with hydrocortisone and/or antihistamines (standard for Fabrazyme) before IV infusion; infusion-related events (ie, fever, rigors, hypertension) may be reduced or eliminated by slower rate of administration or interruption of treatment

FOLLOW-UP

Section 7 of 10

Further Outpatient Care:

• Genetic counseling is necessary for the proband, and a careful pedigree should be obtained to identify all potentially affected family members. Because Fabry disease is an X-linked recessive trait, all daughters of affected males are carriers, and no sons of affected males have the gene for Fabry disease. Typically, mothers of probands are obligate carriers, and their siblings should be considered at risk.

In/Out Patient Meds:

• See Treatment.

Transfer:

• Transfer to a center with specialists familiar with Fabry disease may be indicated.

Deterrence/Prevention:

• Prenatal testing can be performed in women who are pregnant and are carriers of the gene to identify fetuses affected with Fabry disease. A karyotype should be obtained first to identify if the fetus is male. Enzyme activity can then be measured, using either chorionic villus sampling (CVS) or amniotic fluid samples. If the mutation carried in the family is known, DNA can be isolated from CVS or amniotic fluid samples, and genotyping can be performed.

Complications:

• As with all chronic illnesses, patients are at risk for anxiety disorders, depression, or both.

Prognosis:

• Prognosis for patients with Fabry disease has improved with the more widespread use of advanced medical techniques, such as hemodialysis and renal transplant. ERT has demonstrated favorable results in modifying long-term complications of Fabry disease. Early treatment with ERT to prevent irreversible damage to the organs seems reasonable.

MISCELLANEOUS

Section 8 of 10

Medical/Legal Pitfalls:

• Failure to appreciate signs and symptoms of Fabry disease (Most patients with the disease experience long delays from the time the first symptoms appear to the time of diagnosis.)



• Failure to perform appropriate laboratory testing



• Failure to provide genetic counseling

Special Concerns:

• See Deterrence/Prevention for concerns in pregnancy.

TEST QUESTIONS

Section 9 of 10

CME Question 1: A 12-year-old boy experiences pain in his hands and feet during a febrile episode. His maternal uncle is on hemodialysis for kidney failure. Which of the following diagnoses is most likely in the child?

A: Psychogenic pain
B: Cellulitis of the extremities
C: Fabry disease
D: Gaucher disease
E: Ornithine transcarbamylase deficiency

The correct answer is C: The onset of clinical symptoms in persons with Fabry disease typically occurs during late childhood or early adolescence, when acroparesthesias first develop. The pain is likely to occur during febrile episodes. The family history of a maternal uncle with renal failure suggests an X-linked pattern of inheritance.

CME Question 2: A 28-year-old man reports severe pain in his extremities and a tendency to overheat since childhood. Upon physical examination, a slight build, multiple dark-red punctate angiectases in the "bathing suit" region, and moderate pitting edema of the ankles are observed. Which of the following studies is not indicated?

A: Urinalysis
B: Echocardiography
C: Ophthalmologic examination with slit-lamp microscopy
D: Bone densitometry
E: Brain MRI

The correct answer is D: As in this patient, men who are aged 28 years and have classic Fabry disease may also have cardiac, ophthalmologic, renal, and cerebrovascular disease. These organ systems should be evaluated as soon as the diagnosis is confirmed to assess the degree of organ system involvement.

Pearl Question 1 (T/F): A man with Fabry disease has a nonconsanguineous healthy wife who is pregnant with their son. The risk that the son will be affected by Fabry disease is 50%.

The correct answer is False: Fabry disease is inherited in an X-linked fashion; therefore, male-to-male transmission is not possible. The father passes on his X chromosome to all female offspring; thus, all his daughters will be carriers, but his sons will be free of Fabry disease.

Pearl Question 2 (T/F): A man develops renal failure at age 40 years, but his history findings do not include acroparesthesias or hypohidrosis, and no angiokeratomas are detected upon physical examination. Testing for Fabry disease is not indicated in this patient.

The correct answer is False: Patients with the renal variant of Fabry disease may have few to none of the classic signs and symptoms of the disease. Diagnosing the underlying cause of kidney failure is important for many reasons, including providing genetic counseling for the family, providing specific therapy in the patient (eg, enzyme replacement therapy), and ensuring that a suitable noncarrier donor is selected if renal transplantation is needed.

Pearl Question 3 (T/F): Left ventricular hypertrophy is a typical cardiac finding in patients with Fabry disease.

The correct answer is True: Left ventricular hypertrophy is one of the earliest cardiac manifestations of the disease. Interventricular septum hypertrophy, increased dimensions of the aortic root, and valvular regurgitation are other anatomic changes that may be present in the heart. Dysrhythmias are also common.

Pearl Question 4 (T/F): A woman has a son with confirmed Fabry disease. Although the woman is completely asymptomatic, a blood test is ordered for an a-galactosidase enzyme assay. The result is normal, and the son is assumed to have a spontaneous mutation. Testing other family members is not necessary.

The correct answer is False: As a result of random X-chromosome inactivation, female carriers may be asymptomatic. Leukocyte or plasma enzyme activity may range from zero to normal in these women. The use of genotyping or haplotyping to assess carrier status in females is important when results of enzyme testing are nondiagnostic.

BIBLIOGRAPHY

Section 10 of 10

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